An improved process for the preparation of (3r,4r)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine

ABSTRACT

The present invention is related to an improved and efficient process for preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine which comprises:
     (a) N-acylation of 3-Amino-4-methyl pyridine; (b) Quarternization of 3-Acetylamino-4-methyl pyridine using benzyl halide; (c) Partial reduction of quarternized 3-Acetylamino-4-methyl pyridine by Sodium borohydride in Methanol or water; (d) Hydrolysis of partially reduced product to 1-Benzyl-4-methylpiperidin-3-one in presence of acid; (e) Reductive amination of 1-Benzyl-4-methylpiperidin-3-one using Methanolic methylamine in presence of Titanium(IV) isopropoxide in Methanol; (f) Resolution of 1-Benzyl-4-methylpiperidin-3-yl)-methylamine using Ditoluoyl (L) tartaric acid to get (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine. The invention is also related to novel intermediates:   

     
       
         
         
             
             
         
       
     
     wherein R, R′ and X are as described in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase filing of InternationalApplication No. PCT/IB2014/066510, filed on Dec. 2, 2014, designatingthe United States of America and claiming priority to Indian PatentApplication No. 3843/MUM/2013, filed Dec. 9, 2013, and this applicationclaims priority to and the benefit of the above-identified applications,which are all incorporated by reference herein in their entireties.

TECHNICAL FIELD

The present invention provides an efficient and improved process for thepreparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine; akey starting material for the synthesis of3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile.

BACKGROUND OF THE INVENTION

3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile,2-hydroxypropane-1,2,3-tricarboxylate described as FORMULA I below andas disclosed in WO 02/096909, U.S. Pat. No. 7,301,023. US FDA approvedit for rheumatoid arthritis.

The key step for the preparation of3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrileas depicted in (Scheme-1) WO 02/096909 includes:

-   -   (i) resolution of racemic        (1-Benzyl-4-methylpiperidin-3-yl)-methylamine to        (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine using        Di-p-toluoyl-L-tartarate;    -   (ii) condensation of 4-Chlropyrrolo[2,3-d]pyrimidine with        (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine to get        (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine;        and    -   (iii) debenzylation of        (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine        followed by condensation with cyano acetic acid derivative to        get        3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxo-propanenitrile        (FORMULA I), (Scheme-1).

The most important part for the preparation of FORMULA I is thesynthesis of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine as itis very tedious synthesis and also requires very expensive reagent.There are several processes reported in literature for the synthesis andresolution of racemic (1-Benzyl-4-methylpiperidin-3yl)-methylamine to(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine.

WO 2007/012953 discloses preparation of1-Benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide and it'sasymmetric reduction using mixture of Ruthenium and Iridium based chiralcatalysts under hydrogenation condition to provide(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine with 84% cisisomer, having 68% ee.

The patent further discloses the preparation of same intermediate byapplying partial reduction followed by asymmetric reduction approach toobtain highly enriched Piperidine derivative as depicted in Scheme-2.

Both the approaches make use of very high chiral catalyst loading andrender their commercial use expensive and difficult. Further, theprocess requires very high pressure which makes it risky, costlier andunfavorable for scale up.

WO 2010/123919 provides an additional process for preparation of(1-Benzyl-4-methylpiperidin-3-yl)-methylamine, which includes:

-   -   (i) protection of amino group of 3-Amino-4-methyl pyridine with        Dimethyl carbonate in presence of Potassium tert-butoxide in        Tetrahydrofuran;    -   (ii) quaternization of Nitrogen of Pyridine system using Benzyl        bromide in Toluene;    -   (iii) partial reduction of the quaternized Pyridine system to        produce 1,2,5,6-Tetrahydropyridine in presence of Sodium        borohydride in Methanol;    -   (iv) reduction with Platinum oxide in Methanol provides        Piperidine derivative. Followed by the purification by column        chromatography; and    -   (v) further reaction with Lithium aluminium hydride and        purification by column chromatography to get        (1-Benzyl-4-methyl-piperidin-3-yl)-methylamine.

The process has several drawbacks. Overall process yield is very poori.e. approximately 40%. The process uses column chromatography at twostages. Lithium aluminum hydride, a known pyrophoric reagent, accountfor the safety risk during its manufacturing. Lastly Platinum oxide isvery explosive in presence of hydrogen. It is very costly reagent whichdiscourages its use on plant scale. Overall the process is costlier, notso safe to work on commercial scale and demands stringent skill of art.

WO 2010/123919 further reveals an additional procedure for thepreparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine and thesynthetic procedure is summarized in Scheme-3.

Process involves debenzylation and quaternization of ethyl1-Benzyl-3-oxopiperidine-4-carboxylate followed by protection of theresulted Ethyl 3-oxopiperidine-4-carboxylate derivative usingdi-tert-butyl dicarbonate. Protected Piperidine derivative wasmethylated by abstracting the Methylenic proton using Sodium hydride andfurther reaction with Iodomethane. In the next stage deprotection ofN-tert-butoxycarbonyl group was carried out in acidic media, and theresulting 4-Methylpiperidin-3-one was benzylated followed by reductiveamination with Methylamine and Sodium triacetoxyborohydride provide thedesired product (1-Benzyl-4-methylpiperidin-3-yl)-methylamine.

The overall conversion involves five stages from quite a complexstarting material. The process involves protection and deprotection indifferent stages. Use of costly, non safe reagents such as Sodiumhydride and lacrimatic Benzyl bromide and Sodium triacetoxyborohydridelimit its commercial scale production. The process has major draw backwith respect to the use of column chromatography at three stages.Moreover disclosure of process is silent about the purity ofintermediates and of the target molecule produced. The overall yieldmentioned for the process is also very low i.e. 13.6 molar percent.

U.S. Pat. No. 6,627,754 provides a similar reductive amination route asdiscussed in WO 2010/123919 for the synthesis of (1-Benzyl-4-methylpiperidin-3-yl)-methylamine from 1-Benzyl-4-methylpiperidin-3-one in asealed tube using Sodium triacetoxyborohydride as a reducing agent.Sodium triacetoxyborohydride is extremely moisture sensitive pyrophoricreagent. Sealed tube reaction is difficult to execute on large scale.

The processes taught by prior art have several drawbacks namelyexpensive, not suitable for scale up at plant level, energy intensive,difficult, giving lower yields, forcing use of corrosive acids, longerduration of corrosive reactions and less user friendly. Considering thedrawbacks of prior art and very complex methodologies applied, for thepreparation of the (1-Benzyl-4-methyl piperidin-3-yl)-methylamine, thereis a urgent and pressing need for simple, energy economical, financiallycheaper plant friendly process, environment friendly process for thepreparation of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine tosynthesize FORMULA I that does not use hygroscopic and pyrophoricchemicals and yet provides better yields.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an improved andefficient process for the preparation of(1-Benzyl-4-methylpiperidin-3-yl)-methylamine which has better over allyield.

Another object of the invention is to provide a cost effective,environment friendly and energy economic process to prepare(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine

Yet another object of the invention is to provide a process for thesynthesis of (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine toprepare 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]pipridin-1-yl}-3-oxo-propanenitrile,2-hydroxypropane-1,2,3-tricarboxylate (FORMULA I).

According to a first aspect of the present invention an improved andefficient process for the preparation of(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine, of the Formula IIis provided .

Another aspect of the present invention is to provide a process for thepreparation of a compound of Formula Ha, as depicted in Scheme-4,comprising:

-   -   (i) N-acylation of 3-Amino-4-methyl pyridine (Formula III) with        alkyl, aryl or substituted aryl acid anhydride or acid chloride        to get Formula IVa;    -   (ii) quaternization of Nitrogen of Pyridine system having        Formula IVa, using Benzyl or substituted Benzyl halide in an        organic solvent or aqueous solvent or mixture(s) thereof to get        Formula Va;    -   (iii) partial reduction of the optionally isolated quarternized        pyridine system having Formula Va to produce        1,2,5,6-Tetrahydropyridine system of Formula VIa in the presence        of a reducing agent or any Borohydride agent in an organic        solvent or aqueous solvent or mixture(s) thereof, at an ambient        temperature;    -   (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula        VIa in presence of an acid or mixture of acids to get Formula        VIIa, at an ambient temperature;    -   (v) reductive amination of Formula VIIa using Methylamine in        presence of any Lewis acids in an organic solvent or aqueous        solvent or mixture(s) thereof followed by reduction using any        reducing agent or any alkali metal Borohydride derivatives        produce compound of Formula VIIIa, at an ambient temperature;        and    -   (vi) further resolution of compound VIIIa in presence of any        resoluting agent in an organic solvent or aqueous solvent or        mixture(s) thereof produce compound of Formula IIa.

wherein R represents hydrogen, alkyl, aryl, substituted aryl and R′represents aryl or substituted aryl group.

Prior art WO 2010/123919 uses reactants of different class of compounds.The two routes of synthesis (ROS) are dissimilar. WO 2010/123919 doesnot envisage use of anhydride in the first step. The intermediate formedin the reaction of the present invention has a Methyl in the side chainwhich is not the case with prior art. Initial use of different class ofreactants produces different classes of intermediates. Hydrolysis andreductive amination steps and the intermediates formed are unique to theROS of the present invention. These are absent in the prior art. LithiumAluminium Hydride is essential in WO 2010/123919 but is absent inpresent invention. Inventive step of the present invention also residesin surprisingly reduced durations of various reaction steps as comparedto those in WO 2010/123919. Preparation of 1,2,5,6-Tetrahydropyridinesystem of Formula VIa can be completed 30% of time required by WO2010/123919.

Yet another aspect of the present invention is to provide a process forthe preparation of (3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamineof Formula (II), as depicted in Scheme 5, comprising:

-   -   (i) N-acylation of 3-amino-4-methyl pyridine with Acetyl        chloride or Acetic anhydride to get Formula IV;    -   (ii) quaternization of Nitrogen of pyridine system having        Formula IV, using Benzyl chloride in presence of toluene to get        Formula V;    -   (iii) partial reduction of the optionally isolated quaternized        Pyridine system of Formula V to produce        1,2,5,6-Tetrahydropyridine system of Formula VI in presence of        Sodium borohydride in Methanol or water to get Formula VI, at an        ambient temperature;    -   (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula        V in presence of mixture of Hydrochloric acid and Acetic acid to        get Formula VII, at an ambient temperature;    -   (v) reductive amination of Formula VII in presence of        Titanium(IV) tetraisopropoxide in Methylamine followed by        reduction with Sodium borohydride to get        1-Benzyl-4-methylpiperidin-3-yl)-methylamine of Formula VIII, at        an ambient temperature; and    -   (vi) further resolution of compound of Formula VIII in presence        of a resoluting agent such as Dibenzoyl-L-tartaric acid or        Ditoluoyl-L-tartaric acid in the mixture of methanol and/or        water to produce        (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine of the        Formula II.

Reagent : (i) Acetyl chloride, acetic acid, room temperature; (ii)Benzylchloride, toluene, 110° C.; (iii) Sodium borohydride, methanol, 0°C. to 5° C. or sodium borohydride, water, 0° C. to 5° C.; (iv) HCl,AcOH, 80° C. to 85° C.; (v) Titanium(IV) tetraisopropoxide, methanolicmethylamine, NaBH₄, MeOH, 0° C. to 5° C.; (vi) Ditoluoyl-L-tartaricacid, MeOH-water (1:1)

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved and efficient process forthe preparation of compound of formula (IIa) comprising:

-   -   i) N-acylation of 3-amino-4-methyl pyridine (Formula III) with        alkyl, aryl or substituted aryl acid anhydride or acid chloride        to get Formula IVa;    -   (ii) quarternization of Nitrogen of Pyridine system having        Formula IVa, using Benzyl or substituted Benzyl halide in an        organic solvent to get Formula Va;    -   (iii) partial reduction of the quarternized pyridine system        having Formula Va to produce 1,2,5,6-Tetrahydropyridine system        of Formula VIa in presence of a reducing agent or any        Borohydride agent in an organic solvent, at an ambient        temperature;    -   (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula        VIa in presence of acid or mixture of acids to get Formula VIIa,        at an ambient temperature;    -   (v) reductive amination of Formula VIIa using Methylamine in        presence of any Lewis acids in an organic solvent or aqueous        solvent or mixture(s) thereof followed by reduction using any        reducing agent or any alkali metal borohydride derivatives        produce compound of Formula VIIIa, at an ambient temperature;        and    -   (vi) further resolution of compound VIIIa in presence of any        resoluting agent in an organic solvent or aqueous solvent or        mixture(s) thereof produce compound of Formula IIa

C1 acid anhydride is an anhydride of Acetic acid i.e. Acetic anhydride.C2 acid anhydride is an anhydride of Propanoic acid. In the presentinvention one may use anhydrides of C1-10 acids. C1-10 Acid chloride isto be construed as Acid chloride of Formic acid to Decanoic acid, arylacid chlorides or substituted acid chlorides having upto 10 carbonatoms. C1-C05 alcohols are to be construed as Methnol, Ethanol,Propanol, Butanol and Pentanol. Better overall yield is to beinterpreted as overall yield more than 50% for the synthesis of1-Benzyl-4-methylpiperidine-3-yl)-methylamine an intermediate beforeresolution.

Terms quarternization and quaternization are used interchangeably andhave the same meaning with respect to attachments to tertiary Nitrogen.Terms improved and efficient are to be construed in view of betteryields, less energy intensive, reactions of shorter durations besidesreduced costs of inputs and simplicity of the procedures involved,better scalability to plant level. Pyridine system means pyridine ringportion in the molecular structure with or without substituents. Ambienttemperature is to be interpreted as temperature between 0° C. to 30° C.RT is room temperature. Terms Methylene chloride and Methylenedichloride i.e. MDC are used interchangeably. The inventive step of thepresent invention resides in (Scheme-6):

-   -   (i) N-acylation of 3-Amino-4-methyl pyridine (Formula III) with        alkyl, aryl or substituted aryl acid anhydride or acid chloride        to get Formula IVa. Prior art is devoid of acetylation reaction        at this stage. Prior art teaches use of Dimethyl carbonate and        due to difference in reactants of this initial stage,        structurally different intermediates are formed belonging to        different classes of chemical compounds exhibiting different        properties;    -   (ii) quarternization of Nitrogen of Pyridine system having        Formula IVa, using Benzyl or substituted Benzyl halide in an        organic solvent to get Formula Va;    -   (iii) partial reduction of the optionally isolating quarternized        Pyridine system having Formula Va to produce        1,2,5,6-Tetrahydropyridine system of Formula VIa in presence of        a reducing agent or any borohydride agent in an organic solvent        at an ambient temperature;    -   (iv) hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula        VIa in presence of acid or mixture of acids to get Formula VIIa        at an ambient temperature; and    -   (v) reductive amination of Formula VIIa using Methylamine in        presence of any

Lewis acids in an organic solvent or aqueous solvent or mixture(s)thereof followed by reduction using any reducing agent or any alkalimetal borohydride derivatives produce compound of Formula VIIIa at anambient temperature.

wherein R represents hydrogen, alkyl, aryl, substituted aryl and R′represents aryl or substituted aryl group.

-   -   N-acylation of 3-Amino-4-methyl pyridine (Formula III) with        alkyl, aryl or substituted aryl acid anhydride includes C1-10        anhydride, acetic anhydride, and more preferably acetic        anhydride.    -   N-acylation of 3-Amino-4-methyl pyridine (Formula III) with        alkyl, aryl or substituted aryl acid chloride includes C1-10        acid chloride, acetyl chlorides, benzoyl chloride etc. more        preferably acetyl chloride. N acylation leads to formation of        the compound of the formula (IVa) and salts thereof,

-   -   wherein R represents Cl-C10 alkyl, aryl or substituted aryl, but        not including iso-propyl, t-butyl and phenyl. When R represents        C3-C10 alkyl, aryl or substituted aryl, but not including        iso-propyl, t-butyl and phenyl, novel compounds are formed.    -   Quarternization of Nitrogen of Pyridine system having Formula        IVa, using benzyl or substituted benzyl halide includes Benzyl        chloride, Benzyl bromides etc. more preferably benzyl chloride.    -   Quarternization of Nitrogen of Pyridine system having Formula        IVa, to get Formula Va is carried out using Benzyl halide or        substituted benzyl halide in presence of an organic or        aqueous-organic solvent which includes Toluene, Xylenes,        alcoholic solvents, ethereal solvents more preferably Toluene        and Xylenes most preferably Toluene. Polar, protic, aprotic        solvents are to be interpreted as per prevailing definitions.    -   Quarternization of Nitrogen of Pyridine system having Formula        IVa, using benzyl or substituted benzyl halide in presence of an        organic solvent to get Formula Va was carried out at temperature        between 40° C. to 110° C. more preferably between 75° C. to        85° C. A compound of the formula (Va)

wherein R represents alkyl, aryl or substituted aryl more preferablymethyl; R′ represents aryl or substituted aryl group more preferablyphenyl; and X represents halides group such as chloro, bromo, iodo, orany leaving group such as tosyloxy or mesyloxy.

Partial reduction of the quarternized pyridine system of Formula Vaproduces 1,2,5,6-Tetrahydropyridine system of Formula Via, in presenceof a reducing agent such as borohydride agent including Sodiumborohydride, Sodium cyanoborohydride, Sodium triacetoxyborohydride morepreferably Sodium borohydride and the organic solvent selected from thegroup consisting of alcoholic solvents such as Methanol, Ethanolethereal solvents such as Diisopropyl ether (DIPE), Methyl tertiarybutyl ether (MTB) or Toluene, Xylenes or aqueous mixture thereof morepreferably Methanol, water most preferably water. The reduction usingthe borohydride reagent was carried out between 0° C. to 10° C. morepreferably between 0° C. to 5° C.

1,2,5,6-Tetrahydropyridine system of Formula VIa can be obtained fromPyridine system having Formula IVa optionally isolating quarternizedPyridine system having Formula Va. A compound of the formula (VIa) andsalts thereof

wherein R represents alkyl, aryl or substituted aryl more preferablymethyl;

R′ represents aryl or substituted aryl group more preferably phenyl.

Hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula VIa inpresence of an acid or mixture of acids which includes Hydrochloricacid, Sulfuric acid, Phosphoric acid, Trifluoroacetic acid,Trichloroacetic acid, acetic acid or aqueous solutions thereof ormixture(s) thereof more preferably Hydrochloric acid and Acetic acidmost preferably mixture of Hydrochloric acid and Acetic acid.

Hydrolysis of 1,2,5,6-Tetrahydropyridine system of Formula VIa inpresence of an acid or mixture of acids was carried out at temperaturebetween 40° C. to 110° C. more preferably between 75° C. to 90° C. mostpreferably between 85° C. to 90° C.

Reductive amination of Formula VIIa can be carried out by usingMethylamine in presence of any Lewis acids such as AlCl₃, InCl₃,Titanium(IV) tetraisopropoxide, FeCl₃ etc. more preferably Titanium(IV)tetraisopropoxide.

Reductive amination of Formula VIIa can be carried out by usingMethylamine in presence of any Lewis acids in an organic solvent such asalcoholic solvent like Methanol, Ethanol or ethereal solvents likeDi-isopropyl ether (DIPE), Methyl tertiary butyl ether (MTB) or Toluene,Xylenes or aqueous mixture(s) thereof more preferably Methanol or watermost preferably water.

Reductive amination of Formula VIIa using Methylamine in presence of anyLewis acids in an organic solvent followed by reduction using anyreducing agent such as alkali metal borohydride derivatives whichincludes Sodium borohydride, Sodium cyanoborohydride, Sodiumtriacetoxyborohydride more preferably Sodium borohydride to producecompound of Formula VIIIa.

Reductive amination of Formula VIIa using Methylamine in presence of anyLewis acids in an organic solvent followed by reduction using anyreducing agent or any alkali metal borohydride derivatives to getcompound of Formula VIIIa was carried out at temperature between 0° C.to 10° C. more preferably between 0° C. to 5° C.

Resolution of Formula VIIIa in presence of resoluting agent whichincludes Tartaric acid, Dibenzoyl tartaric acid (DBTA), Ditoluoyltartaric acid (DTTA), Mandalic acid, Camphor sulphonic acid etc. morepreferably Dibenzoyl tartaric acid (DBTA), Ditoluoyl tartaric acid(DTTA) most preferably Ditoluoyl tartaric acid (DTTA) to get compound ofFormula IIa

Resolution of compound VIIIa in presence of any resoluting agent in anorganic solvent includes alcoholic solvent such as Methanol, Ethanol,ethereal solvents, Toluene, Xylenes or aqueous mixture(s) thereof, morepreferably methanol to get compound of Formula IIa. Ethereal solventsinclude Di-isopropyl ether (DIPE), Methyl tertiary butyl ether (MTB) butnot limited only to these two solvents. The invention is furtherillustrated by way of the following examples.

EXAMPLES Example-1 Preparation of N-(4-methylpyridin-3-yl)-acetamidefrom 3-Amino-4-methyl pyridine

3-Amino-4-methyl pyridine (200 gm) and Acetic acid (600 mL) were chargedin a 2 L 4-neck round bottom flask with an overhead stirrer and stirredfor 15 minutes at RT. Acetic anhydride (284 gm/263 mL) or Acetylchloride (174 gm) was added drop wise within 1-2 h at that temperature.The reaction mass was then stirred at RT for 8-10 h. After thecompletion of the reaction as monitored by TLC, HPLC; acetic acid wasdistilled out under vacuum. Methanol (1 L) was then added to thereaction mixture and the pH of the reaction mixture was maintainedaround 10-12 by liq. Ammonia. Methanol was distilled out completelyunder vacuum at 50° C. to 55° C. The product was then extracted with MDC(1 L) to get the pure product. Yield: 98% w/w; HPLC Purity: 98%.

Example-2 Preparation of N-(4-methylpyridin-3-yl)-acetamide from3-Amino-4-methyl pyridine

3-Amino-4-methyl pyridine (200 gm) and Acetic anhydride (284 gm/263 mL)in a 2 L 4-neck round bottom flask with an overhead stirrer were stirredfor 15 minutes at RT. The stirring was continued at RT for 1-3 h. Afterthe completion of the reaction as monitored by TLC, Methanol (1 L) wasadded to the reaction mixture and the pH of the reaction mixture wasmaintained around 10-12 by liq. Ammonia. Methanol was distilled outcompletely under vacuum at 50° C. to 55° C. Extraction with MDC (1 L)gave pure product. Yield: 98% w/w; HPLC Purity: 98%.

Example-3 Preparation of N-(4-methylpyridinium-3-yl)-acetamide acetatefrom 3-amino-4-methyl pyridine

3-Amino-4-methyl pyridine (200 gm), Acetic anhydride (284 gm/263 mL) orAcetyl chloride (174 gm) and MDC (1 L) in a 2 L 4-neck round bottomflask with an overhead stirrer were stirred for 15 minuets at RT. Thereaction mass was stirred at RT for 8-10 h. Completion of the reactionwas monitored by TLC, HPLC. Extraction with MDC (1 L) gave pure product.Yield: 98% w/w; HPLC Purity: 98%.

Example-4 Preparation of N-(4-methylpyridin-3-yl)-acetamide from3-Amino-4-methyl pyridine

3-Amino-4-methyl pyridine (200gm), Acetic anhydride (284 gm/263 mL) orAcetyl chloride (174 gm) and MDC (1 L) in a 2 L 4-neck round bottomflask with an overhead stirrer were stirred for 15 minutes at RT. Thereaction mass then stirred at RT for 8-10 h. Completion of the reactionas monitored by TLC. pH of the reaction mixture was maintained around10-12 by liq. Ammonia. Extraction with MDC (1 L) gave pure product.Yield: 98% w/w; HPLC Purity: 98%.

Example-5 Preparation of1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetyl amine fromN-(4-methylpyridin-3-yl)-acetamide

Toluene (1 L) and N-(4-methylpyridin-3-yl)-acetamide (200 gm) werecharged in a 2 L 4-neck round bottom flask with an overhead stirrer andstirred for 15 minutes at RT. Benzyl chloride (202 gm) or Benzyl bromide(273 gm) was added to the insoluble reaction mass and stirred for 15minutes at RT. The temperature of the reaction mass was raised to 80° C.to 85° C. and stirred until the completion of the reaction (monitored byTLC, HPLC). The reaction mass was then cooled to 25° C. to 30° C. anddecanted out the toluene layer. Methanol (1 L) was charged to thereaction mixture, stirred to get clear solution and was cooled to 0° C.to 5° C. Sodium borohydride solution (60 gm in 0.1 N Sodium hydroxide)was added drop wise at 0° C. to 5° C. The reaction mixture was thenstirred for 10-12 h as required to complete the reaction (monitored byTLC, HPLC). Water (600 mL) was added to the reaction mass and stirred toget clear solution. Distilled out Methanol under vacuum. Solidprecipitation observed was filtered by Buckner funnel to get the pureproduct. (Yield =84-87%; HPLC: 90%).

Example-6 Preparation of1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetyl amine fromN-(4-methylpyridin-3-yl)-acetamide

Toluene (1 L), N-acetyl-3-amino-4-methyl pyridine (200 gm) were chargedin a 2 L 4-neck round bottom flask with an overhead stirrer and stirredfor 15 minutes at RT. Benzyl chloride (202 gm) or Benzyl bromide (273gm) was added to the insoluble reaction mass and stirred for 15 minutesat that temperature. The temperature of the reaction mass was thenraised to 80° C. to 85° C. and stirred the reaction mixture at thattemperature for 8-10 h as required to complete the reaction (monitoredby TLC, HPLC). The reaction mass was cooled to 25° C. to 30° C. Water (1L) was charged to the reaction mixture and stirred for 15 minutes.Separated out aqueous layer and cooled it to 0° C. to 5° C. Sodiumborohydride solution (60 gm in 0.1 N Sodium hydroxide) was then addedinto the aqueous layer drop wise at 0° C. to 5° C. The reaction mixturewas then stirred for 10-12 h to complete the reaction (monitored by TLC,HPLC). After the completion of the reaction solid precipitation observedwas filtered by Buckner funnel to get the pure product. (Yield =84-87%;HPLC: 90%)

Example-7 Preparation of benzyl quarternized salt ofN-(4-methylpyridin-3-yl)-acetamide

Toluene (1 L), N-(4-methylpyridin-3-yl)-acetamide (200 gm) were chargedin a 2 L 4-neck round bottom flask with an overhead stirrer and stirredfor 15 minutes at RT. Benzyl chloride (202 gm) or Benzyl bromide (273gm) was added into the insoluble reaction mass and stirred for 15minutes at that temperature. The temperature of the reaction mass wasthen raised to 80° C. to 85° C. and stirred for 8-10 h to complete thereaction (monitored by TLC, HPLC). The reaction mass was then cooled to25° C. to 30° C. and filtered off the Toluene layer to get pure benzylquarternized salt of N-(4-methylpyridin-3-yl)-acetamide (Yield =98%;HPLC: 95%)

Example-8 Preparation of1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine from benzylquarternized salt of N-(4-methylpyridin-3-yl)-acetamide

Methanol (1 L), benzyl quarternized salt ofN-(4-methylpyridin-3-yl)-acetamide (200 gm) were charged in a 2 L 4-neckround bottom flask with an overhead stirrer and stirred for 15 minutesat RT. Cooled the reaction mixture to 0° C. to 5° C. and added Sodiumborohydride solution (60 gm in 0.1 N Sodium hydroxide) drop wise at thattemperature. Stirred for 10-12 h to complete the reaction (monitored byTLC, HPLC). After the completion of the reaction, water (600 mL) wasadded and stirred to get clear solution. Distilled out methanol undervacuum. Solid precipitation observed was filtered to get the pureproduct. (Yield =75%; HPLC: 98%).

Example-9 Preparation of1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine from3-amino-4-methyl pyridine

3-Amino-4-methyl pyridine (200 gm) and Acetic anhydride (284 gm/263 mL)were charged in a 2 L 4-neck round bottom flask with an overhead stirrerand stirred at 25° C. to 30° C. for 1-3 h. After the completion of thereaction as monitored by TLC, methanol (1 L) was added to the reactionmixture and the pH maintained around 10-12 by liq. Ammonia. Methanol wasdistilled out completely under vacuum at 50° C. to 55° C. The productwas then extracted with MDC (1 L) and distilled out the organic layer toget crude N-(4-methylpyridin-3-yl)-acetamide.

Toluene (1 L) was charged to the reaction mixture and stirred for 15minutes at RT. Benzyl chloride (202 gm) or Benzyl bromide (273 gm) wasadded into the insoluble reaction mass and stirred for 15 minutes atthat temperature The temperature was then raised to 80° C. to 85° C. andstirred the reaction mixture at that temperature for 8-10 h as requiredto complete the reaction (monitored by TLC, HPLC). The reaction mass wascooled to 25° C. to 30° C. Water (1 L) was then charged to the reactionmixture and stirred for 15 minutes. Separated out aqueous layer andcooled it to 0° C. to 5° C. Sodium borohydride solution (60 gm in 0.1NSodium hydroxide) was added into the aqueous layer drop wise at 0° C. to5° C. The reaction mixture was then stirred for 10-12 h as required tocomplete the reaction (monitored by TLC, HPLC). After the completion ofthe reaction solid precipitation observed was filtered by Buckner funnelto get the pure product. (Yield =84-87%; HPLC: 90%).

Example-10 Preparation of N-Benzyl-4-methylpiperidin-3-one from1-Benzyl-4-methyl-1,4,5,6-tetrahydropyridin-3-yl-acetylamine

Acetic acid (50 mL), Conc. HC1 35% (100 mL) were charged in a 2 L 4-neckround bottom flask with an overhead stirrer and stirred for 10 minutesat RT. 1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100gm) was then added into the reaction mass at that temperature.Temperature of the reaction mixture was raised slowly to 85° C. to 90°C. and stirred for 3-4 h at that temperature as required to complete thereaction (monitored by TLC, HPLC). The reaction mixture was cooled to25° C. to 30° C. and extracted with Toluene (500 mL) to get the pureproduct. Yield: 95%; HPLC: 95%

Example-11 Preparation of N-Benzyl-4-methylpiperidin-3-one from1-Benzyl-4-methyl-1,4,5,6-tetrahydropyridin-3-yl-acetylamine

Conc. HCl 35% (150 mL) and1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine (100 gm)were charged in a 2 L 4-neck round bottom flask with an over-headstirrer and stirred for 10 minutes at RT. Temperature of the reactionmixture was raised slowly to 85° C. to 90° C. and stirred for 3-4 h tocomplete the reaction (monitored by TLC, HPLC). The reaction mixture wasthen cooled to 25° C. to 30° C. and extracted with Toluene (500 mL) toget the pure product. Yield: 95%; HPLC: 90%.

Example-12 Preparation of N-Benzyl-4-methylpiperidin-3-one from1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl-acetylamine

Acetic acid (100 mL) and1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridine-3-yl-acetylamine (100 gm)were charged in a 2 L 4-neck round bottom flask with an overhead stirrerand stirred for 15 minutes at RT. Temperature of the reaction mixturewas raised slowly to 85° C. to 90° C. and stirred for 3-4 h to completethe reaction (monitored by TLC, HPLC). The reaction mixture was thencooled to 25° C. to 30° C. and extracted with toluene (500 mL) to getthe pure product. Yield: 95%; HPLC: 90%.

Example-13 Preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylaminefrom N-Benzyl-4-methylpiperidin-3-one

Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100 gm) werecharged in a 2 L 4-neck round bottom flask with an overhead stirrer andstirred for 15 minutes at RT. The reaction mass was cooled to 0° C. to5° C. and Titanium(IV) tetraisopropoxide solution (175 mL) was addeddrop wise within 30-45 minutes. The reaction mass was stirred at 0° C.to 5° C. for 30 minutes and Methanolic methylamine solution (30%) (100mL) was added drop wise at 0° C. to 5° C. within 30-45 minutes. Thereaction mass was stirred for 2-3 h at 0° C. to 5° C. Sodium borohydride(22 gm) was then added to the reaction mass within 30-45 minutes at 0°C. to 5° C. and stirred for 2-3 h. After the completion of the reactionas monitored by TLC, HPLC; water (500 mL) was added to the reactionmixture and stirred for 30-45 minutes at RT. The product was extractedusing MDC (500 mL) to get the pure product. Yield: 90%; HPLC: 90%.

Example-14 Preparation of (1-Benzyl-4-methylpiperidin-3-yl)-methylaminefrom N-Benzyl-4-methyl-3-piperidone

Methanol (500 mL) and N-Benzyl-4-methylpiperid-3-one (100 gm) werecharged in a 2 L 4-neck round bottom flask with an overhead stirrer.Stirred for 15 minutes at RT. The reaction mass was cooled to 0° C. to5° C. and Titanium(IV) tetraisopropoxide solution (175 mL) was addeddrop wise within 30-45 minutes. The reaction mass was stirred at 0° C.to 5° C. for 30 minutes and Methylamine hydrochloride (66 gm) was addedat 0° C. to 5° C. within 30-45 minutes. The reaction mass was stirredfor 2-3 h at 0° C. to 5° C. Sodium borohydride (22 gm) was added to thereaction mass within 30-45 minutes at 0° C. to 5° C. and stirred for 2-3h. After the completion of the reaction as monitored by TLC, HPLC; water(500 mL) was added to the reaction mass and stirred for 30-45 minutes atRT. The product was extracted by using MDC (500 mL) to get the pureproduct. Yield: 95%; HPLC: 90%.

Example-15 Resolution of (1-Benzyl-4-methylpiperidin-3-yl)-methylamineto get (3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine

Methanol (500 mL) and (1-Benzyl-4-methylpiperidin-3-yl)-methylamine (100gm) were charged in a 2 L 4-neck round bottom flask with an overheadstirrer and stirred for 15 minutes at RT. Ditoluoyl-L-tartaric acid(DTTA) (106 gm) or Dibenzoyl-L-tartaric acid (DBTA) (98 gm) was added tothe reaction mixture and stirred for 15 minutes to get clear solution.Water (500 mL) was added to the reaction mass and the temperature wasraised to 65° C. to 70° C. and stirred for 1 h. The reaction mass wascooled to 10° C. to 15° C. and maintained for 3h. The solid precipitatedwas filtered off to get pure Ditoluoyl-L-tartaric acid (DTTA) orDibenzoyl-L-tartaric acid (DBTA) salt of(3R,4R)-(1-Benzyl-4-methylpiperidin-3-yl)-methylamine. Yield =80-82%;HPLC: 98%.

Although the present invention recites various specific embodiments, itis not meant to be construed in a limiting sense. Various modificationsof the disclosed embodiments and alternate embodiments will becomeapparent to persons skilled in the art upon reference to the presentinvention. It is therefore contemplated that such modifications can bemade without departing from the true spirit or scope of the presentinvention as exemplified and claimed herein below.

1. A process for the preparation of(3R,4R)-(1-benzyl-4-methylpiperidin-3-yl)-methylamine (Formula IIa)comprising: (i) N-acylation of 3-Amino-4-methyl pyridine (Formula III)with alkyl, aryl or substituted aryl acid chloride or acid anhydride toprepare a compound of the Formula IVa and optionally isolating it; (ii)quarternization of Nitrogen of the Pyridine system in a compound of theFormula IVa, using benzyl or substituted aryl benzyl halide in anorganic solvent to prepare a compound of the Formula Va and optionallyisolating it; (iii) partial reduction of a compound of the Formula Va toproduce 1,2,5,6-Tetrahydropyridine system of a compound of the FormulaVIa in presence of a reducing agent or any alkali metal borohydrideagent in a suitable solvent, at an ambient temperature; (iv) hydrolysisof 1,2,5,6-Tetrahydropyridine system of a compound of the Formula VIa inpresence of an acid or mixture of acids to prepare a compound of theFormula VIIa at an ambient temperature; (v) reductive amination of acompound of the Formula VIIa using Methylamine in presence of any Lewisacid in an organic solvent or an aqueous solvent or mixture(s) thereoffollowed by reduction using any reducing agent or any alkali metalborohydride derivatives to prepare a compound of the Formula VIIIa at anambient temperature; and (vi) further resolution of a compound of theformula VIIIa in presence of any resoluting agent in an organic solventor an aqueous solvent or mixture(s) thereof to prepare the compound ofFormula IIa.
 2. The process for the preparation of(1-Benzyl-4-methylpiperidin-3-yl)-methylamine of the Formula VIIIacomprising the process as claimed in claim 1 (i) to claim 1 (v).
 3. Theprocess of claim 1, wherein the alkyl, aryl or substituted aryl acidanhydride of step (i) comprises an anhydride of C1-10 acids.
 4. Theprocess of claim 1, according to claim 1(i) wherein the alkyl, aryl orsubstituted aryl acid chloride of step (i) comprises a C1-10 Acidchloride, Acetyl chloride, or Benzoyl chloride.
 5. The process of claim1, wherein the benzyl or substituted aryl benzyl halide of step (ii) isselected from the group consisting of—Benzyl chloride, Benzyl bromide,substituted Benzyl chloride and substituted Benzyl bromide.
 6. Theprocess of claim 1, wherein the solvent of step (ii) is selected fromthe group consisting of aromatic, polar aprotic, non-polar solvents,ethers, esters, ketonic solvents, water or mixture(s) thereof.
 7. Theprocess of claim 6, wherein the solvent is selected from the groupconsisting of Toluene, Xylenes, Cyclohexane, water or mixture(s)thereof.
 8. The process of claim 7, wherein the solvent is selected fromToluene or Xylene or mixture thereof.
 9. The process of claim 1, whereinthe alkali metal borohydrides of steps (iii) and (v) are selected fromthe group consisting of Sodium borohydride, Sodium cyanoborohydride, orSodium triacetoxyborohydride.
 10. The process of claim 1, wherein thesuitable solvent of step (iii) is selected from the group consisting ofwater, C1-C5 alcohol or mixture(s) thereof.
 11. The process of claim 1,wherein the acid or mixture of acids of stealiy) is selected from thegroup consisting of Hydrochloric acid, Sulfuric acid, Phosphoric acid,Trifluoroacetic acid, Trichloroacetic acid, substituted halo aceticacid, Acetic acid, HI, HBr, mineral acids, organic acids or aqueoussolutions thereof or mixture(s) thereof.
 12. The process of claim 1,wherein the Lewis acid of step (v) is selected from the group consistingof—Aluminium trichloride, Ferric chloride, Zinc chloride, Indiumchloride, Titanium(IV) tetraisopropoxid.
 13. The process of claim 1,wherein the resoluting agent of step (vi) is selected from the groupconsisting of Dibenzoyl tartaric acid, Ditoluoyl tartaric acid, Tartaricacid, Mandelic acid, or Camphor sulphonic acid.
 14. The compound of theformula (IVa) and salts thereof,

wherein R represents C3-C10 alkyl, aryl or substituted aryl, but notincluding iso-propyl, t-butyl and phenyl.
 15. A compound of the formula(Va).

wherein R represents alkyl, aryl or substituted aryl; R′ represents arylor substituted aryl group; and X represents halides group selected fromchloro, bromo, iodo, or any leaving group selected from tosyloxy ormesyloxy.
 16. A compound of the formula (VIa) and salts thereof.

wherein R represents alkyl, aryl or substituted aryl; R′ represents arylor substituted aryl group.
 17. The process of claim 1, wherein thehydrolysis in step (iv) is carried out at a temperature in the rangefrom 40° C. to 100° C., preferably from 50° C. to 95° C. and the morepreferably from 60° C. to 95° C.